Base de datos multicéntrica de hemorragia subaracnoidea espontánea del Grupo de Trabajo de Patología Vascular de la Sociedad Española de Neurocirugía: presentación,criterios de inclusión y desarrollo de una base de datos en internet = Spontaneous Subarachnoid Haemorrhage multicenter database from the Group for the Study of Vascular Pathology of the Spanish Society for Neurosurgery: Presentation, inclusion criteria and development of an internet-based registry

Introducción. La hemorragia subaracnoidea (HSA) continúa siendo una de las enfermedades de interés neuroquirúrgico de más alta morbilidad y mortalidad. Su estudio es clave a la hora de mejorar la atención de estos enfermos en nuestro medio. Con este fin el Grupo de Trabajo de Patología Vascular de la SENEC decidió la creación de una base de datos multicéntrica para su estudio. Material y métodos. Se incluyen en esta base de datos todos los casos de hemorragia subaracnoidea espontánea ingresados en los centros participantes de forma prospectiva desde Noviembre del año 2004 hasta Noviembre del 2007. Se decidieron de forma consensuada los campos a recoger incluyendo edad, antecedentes personales, características clínicas, características radiológicas y del aneurisma, tipo de tratamiento y complicaciones de la enfermedad, evolución según la escala de evolución de Glasgow (GOS) al alta y a los seis meses así como el resultado angiográfico del tratamiento. Todos los campos se recogieron en un formulario rellenable a través de una página web segura. Resultados. En los tres años en los que ha estado activa la base se han recogido un total de 1149 casos de HSA espontánea recogidos por 14 centros participantes. Se ha estimado que es necesario aproximadamente un tiempo de 3.4 minutos para rellenar cada caso. En cuanto a sus características generales la serie es similar a otras series hospitalarias no seleccionadas. La edad media de los enfermos incluidos es de unos 55 años y la relación mujer:hombre 4:3. En cuanto a la gravedad del sagrado inicial un 32% de los enfermos se encontraba en mal grado clínico (WFNS = 4 ó 5). El 5% de los pacientes fallecieron antes de realizarse una angiografía que confirmara el origen aneurismático del sangrado. Se confirmó el origen aneurismático en el 76% de los pacientes mientras que en el 19% no se encontró ninguna lesión vascular responsable del sangrado, siendo clasificados como HSA idiopática. En los pacientes en los que se detectó un aneurisma su tratamiento fue endovascular en el 47% de los casos, quirúrgico en el 39, mixto en el 3% y no recibieron tratamiento de su aneurisma el 11% de los pacientes por fallecimiento precoz. En cuanto a su evolución, la mortalidad global de la serie se sitúa en el 22%. Sólo el 40% de los enfermos con HSA aneurismática presentaron una buena evolución (GOS=5). Conclusiones. La HSA espontánea continúa siendo una enfermedad con alta morbilidad y mortalidad. Esta base de datos puede ser un instrumento para conocer mejor sus características en nuestro medio y mejorar sus resultados, ya que se trata de una serie multicéntrica hospitalaria no seleccionada. Sería pues recomendable que esta base constituyera el germen de un registro nacional de HSA espontánea. Introduction. Subarachnoid haemorrhage is one of the most severe neurosurgical diseases. Its study is crucial for improving the care of these patients in our environment. With this goal the Group for the Study of Neurovascular Pathology of the Spanish Society for Neurosurgery (SENEC) decided to create a multicenter registry for the study of this disease. Materials and methods. In this database we have prospectively included all cases with spontaneous subarachnoid haemorrhage admitted to the participant hospitals from November 2004 to November 2007. The fields to be included in the database were selected by consensus, including age, past medical history, clinical characteristics at admission, radiological characteristics including presence or absence of an aneurysm and its size and location, type and complications of the aneurysm treatment, outcome assessed by the Glasgow Outcome Scale (GOS) at discharge and six months after the bleeding as well as the angiographic result of the aneurysm treatment. All fields were collected by means of an electronic form posted in secure web page. Results. During the three years of study a total of 1149 patients have been included by 14 Hospitals. The time needed to fill in a patient in the registry is approximately 3.4 minutes. This series of patients with spontaneous SAH is similar to other non-selected in-hospital series of SAH. The mean age of the patients is 55 years and there is a 4:3 female to male ratio. In relation to the severity of the bleeding 32% of the patients were in poor clinical grade at admission (WFNS 4 or 5). 5% of the patients died before angiography could be performed. An aneurysm was confirmed as the origin of the bleeding in 76% of the patients (aSAH), while in 19% of the patients no lesion was found in the angiographic studies and were thus classified as idiopathic subarachnoid hemorrhage (ISAH). Of those patients with aSAH, 47% were treated endovascularly, 39% surgically, 3% received a combined treatment and 11% did not receive any treatment for their aneurysm because of early death. Regarding outcome, there is a 22% mortality in the series. Only 40% of the patients with aSAH reached a good outcome at discharge (GOS = 5). Conclusions. Spontaneous SAH continues to be a disease with high morbidity and mortality. This database can be an ideal instrument for improving the knowledge about this disease in our environment and to achieve better results. It would be desirable that this database could in the future be the origin of a national registry of spontaneous SAH

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for drug-induced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS: We associated DILI with rs114577328 (a proxy for A*33:01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9-3.8; P = 2.4 × 10-8) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6-2.5; P = 9.7 × 10-9). The association with A*33:01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A*33:01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6-2.7; P = 4.8 × 10-9). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0-9.5; P = 7.1 × 10-9). We validated the association between A*33:01 terbinafine- and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A*33:01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors

Association of Liver Injury From Specific Drugs, or Groups of Drugs, With Polymorphisms in HLA and Other Genes in a Genome-Wide Association Study

BACKGROUND & AIMS: We performed a genome-wide association study (GWAS) to identify genetic risk factors for druginduced liver injury (DILI) from licensed drugs without previously reported genetic risk factors. METHODS: We performed a GWAS of 862 persons with DILI and 10,588 population-matched controls. The first set of cases was recruited before May 2009 in Europe (n = 137) and the United States (n = 274). The second set of cases were identified from May 2009 through May 2013 from international collaborative studies performed in Europe, the United States, and South America. For the GWAS, we included only cases with patients of European ancestry associated with a particular drug (but not flucloxacillin or amoxicillin-clavulanate). We used DNA samples from all subjects to analyze HLA genes and single nucleotide polymorphisms. After the discovery analysis was concluded, we validated our findings using data from 283 European patients with diagnosis of DILI associated with various drugs. RESULTS: We associated DILI with rs114577328 (a proxy for A* 33: 01 a HLA class I allele; odds ratio [OR], 2.7; 95% confidence interval [CI], 1.9 - 3.8; P = 2.4 x 10(-8)) and with rs72631567 on chromosome 2 (OR, 2.0; 95% CI, 1.6 - 2.5; P = 9.7 x 10(-9)). The association with A* 33: 01 was mediated by large effects for terbinafine-, fenofibrate-, and ticlopidine-related DILI. The variant on chromosome 2 was associated with DILI from a variety of drugs. Further phenotypic analysis indicated that the association between DILI and A* 33: 01 was significant genome wide for cholestatic and mixed DILI, but not for hepatocellular DILI; the polymorphism on chromosome 2 was associated with cholestatic and mixed DILI as well as hepatocellular DILI. We identified an association between rs28521457 (within the lipopolysaccharide-responsive vesicle trafficking, beach and anchor containing gene) and only hepatocellular DILI (OR, 2.1; 95% CI, 1.6 - 2.7; P = 4.8 x 10(-9)). We did not associate any specific drug classes with genetic polymorphisms, except for statin-associated DILI, which was associated with rs116561224 on chromosome 18 (OR, 5.4; 95% CI, 3.0 - 9.5; P = 7.1 x 10(-9)). We validated the association between A* 33: 01 terbinafine-and sertraline-induced DILI. We could not validate the association between DILI and rs72631567, rs28521457, or rs116561224. CONCLUSIONS: In a GWAS of persons of European descent with DILI, we associated HLA-A* 33: 01 with DILI due to terbinafine and possibly fenofibrate and ticlopidine. We identified polymorphisms that appear to be associated with DILI from statins, as well as 2 non-drug-specific risk factors.Peer reviewe

A global research priority agenda to advance public health responses to fatty liver disease

BACKGROUND & AIMS: An estimated 38% of adults worldwide have non-alcoholic fatty liver disease (NAFLD). From individual impacts to widespread public health and economic consequences, the implications of this disease are profound. This study aimed to develop an aligned, prioritised fatty liver disease research agenda for the global health community. METHODS: Nine co-chairs drafted initial research priorities, subsequently reviewed by 40 core authors and debated during a three-day in-person meeting. Following a Delphi methodology, over two rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the priorities, via Qualtrics XM, indicating agreement using a four-point Likert-scale and providing written feedback. The core group revised the draft priorities between rounds. In R2, panellists also ranked the priorities within six domains: epidemiology, models of care, treatment and care, education and awareness, patient and community perspectives, and leadership and public health policy. RESULTS: The consensus-built fatty liver disease research agenda encompasses 28 priorities. The mean percentage of 'agree' responses increased from 78.3 in R1 to 81.1 in R2. Five priorities received unanimous combined agreement ('agree' + 'somewhat agree'); the remaining 23 priorities had >90% combined agreement. While all but one of the priorities exhibited at least a super-majority of agreement (>66.7% 'agree'), 13 priorities had 90% combined agreement. CONCLUSIONS: Adopting this multidisciplinary consensus-built research priorities agenda can deliver a step-change in addressing fatty liver disease, mitigating against its individual and societal harms and proactively altering its natural history through prevention, identification, treatment, and care. This agenda should catalyse the global health community's efforts to advance and accelerate responses to this widespread and fast-growing public health threat. IMPACT AND IMPLICATIONS: An estimated 38% of adults and 13% of children and adolescents worldwide have fatty liver disease, making it the most prevalent liver disease in history. Despite substantial scientific progress in the past three decades, the burden continues to grow, with an urgent need to advance understanding of how to prevent, manage, and treat the disease. Through a global consensus process, a multidisciplinary group agreed on 28 research priorities covering a broad range of themes, from disease burden, treatment, and health system responses to awareness and policy. The findings have relevance for clinical and non-clinical researchers as well as funders working on fatty liver disease and non-communicable diseases more broadly, setting out a prioritised, ranked research agenda for turning the tide on this fast-growing public health threat

A global action agenda for turning the tide on fatty liver disease

BACKGROUND AND AIMS: Fatty liver disease is a major public health threat due to its very high prevalence and related morbidity and mortality. Focused and dedicated interventions are urgently needed to target disease prevention, treatment, and care. APPROACH AND RESULTS: We developed an aligned, prioritized action agenda for the global fatty liver disease community of practice. Following a Delphi methodology over 2 rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the action priorities using Qualtrics XM, indicating agreement using a 4-point Likert-scale and providing written feedback. Priorities were revised between rounds, and in R2, panelists also ranked the priorities within 6 domains: epidemiology, treatment and care, models of care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus fatty liver disease action agenda encompasses 29 priorities. In R2, the mean percentage of "agree" responses was 82.4%, with all individual priorities having at least a super-majority of agreement (> 66.7% "agree"). The highest-ranked action priorities included collaboration between liver specialists and primary care doctors on early diagnosis, action to address the needs of people living with multiple morbidities, and the incorporation of fatty liver disease into relevant non-communicable disease strategies and guidance. CONCLUSIONS: This consensus-driven multidisciplinary fatty liver disease action agenda developed by care providers, clinical researchers, and public health and policy experts provides a path to reduce fatty liver disease prevalence and improve health outcomes. To implement this agenda, concerted efforts will be needed at the global, regional, and national levels

Sarcopenia in the setting of nonalcoholic fatty liver

Nonalcoholic fatty liver is a worldwide common problem with more prevalence in non-Asian populations that is closely correlated with the muscle-related disorder sarcopenia. The incidence of both health issues has been observed to be strongly interlinked where presence of one exacerbates the other. Nonalcoholic fatty liver disease (NAFLD) pathophysiology increases the muscle loss, while the onset of NAFLD in sarcopenic patients aggravates the liver problems as compared to non-sarcopenic patients. Scarcity of research on the subject provides very little evidence about the cause and effect of disorders. No FDA approved drugs are available to date for NAFLD and sarcopenia. Research is underway to understand the complex biochemical pathways involved in the development of both disorders. This review is a small contribution toward understanding sarcopenia in the setting of NAFLD that provides insight on the common pathophysiological profile of sarcopenia and NAFLD and portrays a novel way of delving into the subject by introducing the concept of cortisol crosstalk with the muscle-liver axis. Sarcopenia and NAFLD are considered metabolism-related problems, and cortisol, being a glucocorticoid, plays an important role in metabolism of fats, carbohydrates, and proteins. Cushing’s syndrome, characterized by abnormally elevated concentrations of blood cortisol/enhanced intracellular activity, shares many pathologic conditions (such as insulin resistance, metabolic syndrome, abnormal levels of specific cytokines, and obesity) with NAFLD and sarcopenia. Hence, cortisol can be a potential biomarker in sarcopenia and NAFLD. As cortisol activity at cellular level is controlled by 11β-hydroxysteroid dehydrogenase type 1 and 2 (11β-HSD1/2) enzymes that convert inactive steroid precursor into active cortisol, these enzymes can be targeted for the study of sarcopenia and NAFLD. Combined studies on NAFLD and sarcopenia with respect to cortisol open a new avenue of research in the understanding of both disorders